Recent advances in surgical methods and the development of blood substitutes have permitted surgeons to carry out extremely time-consuming and complicated surgical procedures in which the subject's body temperature is lowered to minimize damage to the subject's brain and vital organs. Lowering the temperature of an euthermic subject to a temperature well below that normally homeostatically maintained by the subject reduces the metabolic rate, which in course, decreases the demands for oxygen and glucose of the vital tissues and organs. This is particularly important for carrying out procedures on the organs of the central nervous system, which require large amounts of glucose and oxygen. Consequently, while time-consuming and complicated procedures, such as neurosurgery and cardiovascular procedures can be carried out, however, time constraints are still an important factor in such procedures.
A number of blood substitutes have been developed in the past. These blood substitutes have been used primarily as hypothermic preservation solutions for transplantable organs and tissues, which are surgically removed from donors to be later transplanted. The majority of blood substitutes used in organ preservation are solutions of substances that readily permeate the vasculature of the subject's or donor's organs and consequently, are not very useful in surgery on living subjects. Examples of blood substitutes containing primarily vasculature permeable substances include the blood substitutes of Collins, et al., Lancet 1219-1222 (1969), Collins G. M., Transplant. Proc. IX. 1529 (1977), Fischer, et al., Transplantation 21:498 (1976), Sacks, et al., Transplantation 19:283 (1974), Kallerhoff, et al., Transplantation, 39:5, 485-489 (1985) and Klebanoff and Phillips, Cryobiology, 6:121-125 (1969). Each of these blood substitutes contain only low molecular weight molecules, which are capable of passing through the vasculature of the subject and consequently, are ineffective at maintaining proper ionic or fluid balance or plasma volume for extended periods of time.
Wall, et al. disclose blood substitutes useful for cryostatic preservation of organs and tissues for implantations containing human serum albumin as an impermeable substance to maintain volume. (Transplantation 23:210 (1977)). This plasma-based blood substitute requires the processing of human blood and consequently, exposes subjects to the risk of infection by blood transmitted diseases, such as hepatitis A, B or non-A-non-B virus or the AIDS virus. Clearly it is desirable to use non-blood based blood substitutes.
Non-blood based blood substitutes useful for preserving organs and tissues for transplant are disclosed by Breton, Jr. (U.S. Pat. No. 4,920,044) and Belzer, et al. (U.S. Pat. No. 4,879,283 and U.S. Pat. No. 4,798,824). Breton, Jr.'s hyperosmotic intracellular organ flush and maintenance solutions contain neither colloids for oncotic support nor lactobionate to maintain cellular anion and hydraulic balance. Belzer's solutions for organ preservation contain impermeants and colloids for osmotic support, however, patentees' solution contains concentrations of potassium ions and sodium ions of 120 mM and 30 mM, respectively. These concentrations of ions are within the range of normal intracellular values and consequently, passive diffusional loss of cellular potassium and gain of sodium are inhibited or compensated for. These ionic concentrations are not applicable to whole body hypothermic blood substitutes in view of evidence that high potassium levels induce necrosis in myocardial tissue (contraction-band necrosis). Also, much lower potassium levels (e.g. less than 10 mM) are needed in order to reactivate the heart during rewarming.
Solutions used as blood substitutes for surgery on living subjects are formulated with different criteria than those blood substitute solutions used in organ preservation. For example, during protracted surgical procedures it is essential to maintain body fluid balance between the subject's vasculature and interstitial spaces of the cells. It is also necessary to maintain the subject's blood pH during surgery. Segall, et al. (U.S. Pat. No. 4,923,422) disclose a four-solution blood substitute useful in hypothermic preservation of isolated organs for use in transplantations, as well as in bloodless surgery using whole body hypothermia. Patentees disclose blood substitute solutions containing varying levels of dextrose depending on the surgical procedure for which the blood substitute is used. However, patentees specifically note that use of mannitol is to be avoided when the blood substitute is administered to living subjects because use of this sugar is associated with significant decreases in pH that are usually uncontrollable even with dialysis. Patentees disclose that recovery of a subject that had been perfused with the four solution blood substitute was slow, with the animal unable to stand for the first post-operative month.
Clearly, a blood substitute that provides the benefits of prolonged preservation time as required by organ storage preservation solutions and which protects the brain and visceral organs during controlled hypothermia is desired. Major benefits for protracted surgical procedures such as certain neurosurgical and cardiovascular procedures would be realized if the time constraints of approximately one hour, imposed by present technologies for cardiac arrest during hypothermia could be extended without significant ischemic injury. Moreover, it is also desired that recovery of the subject after bloodless surgery be very fast.